0-(2,3-Epoxypropyl)-hydroximic acid esters

ABSTRACT

Compounds of general formula ##STR1## wherein R 1  represents a radical selected from the group consisting of an alkyl group having from 1 to 6 carbon atoms, an unsubstituted aryl group having 6 carbon atoms, an aryl group having 6 carbon atoms being substituted by at least one radical selected from the group consisting of a chlorine atom, alkyl and alkoxy each having up to 2 carbon atoms; and R 2  represents an alkyl group having from 1 to 6 carbon atoms.

This invention relates to novel O-(2,3-epoxypropyl)-hydroximic acidesters and processes for their preparation.

According to one aspect of the present invention there are providedcompounds of general formula ##STR2## wherein R¹ represents astraight-chained or branched alkyl group having from 1 to 6 carbonatoms, or an aryl group having up to 6 carbon atoms optionallysubstituted by one or more chlorine atoms or alkyl or alkoxy groupshaving up to 2 carbon atoms; and R² represents an alkyl group havingfrom 1 to 6 carbon atoms.

The compounds according to the present invention are valuableintermediates for the synthesis of 3-substitutedO-(2-hydroxypropyl)-hydroxylamines which have interesting biological andpharmacological properties.

In compounds of general formula I in which the aryl radical issubstituted, the aryl group generally has from 1 to 3 identical ordifferent substituents selected from alkyl and alkoxy groups having upto 2 carbon atoms and chlorine atoms. The groups R¹ and R² in thecompounds according to he invention may be the same or different, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert.-butyl, and the various pentyl and hexyl groups. When R¹ representsan aryl group, these groups may be, for example phenyl, tolyl orchlorophenyl groups. R¹ and R² are, however, preferably alkyl groupswith 1 to 4 carbon atoms and R¹ is also preferably an aromatichydrocarbon radical.

Especially useful compounds according to the invention are:

ETHYL O-(2,3-epoxypropyl)-acetohydroximate; and

METHYL O-(2,3-epoxypropyl)-benzohydroximate.

It is not possible to prepare the compounds of general formula Idirectly from hydroxylamine per se, as it is known that selectiveO-alkylation of hydroxylamine is only successful when the morenucleophilic amino group is blocked. This may be effectively achieved byforming the hydroximic acid esters of formula ##STR3## (in which R¹ andR² are as hereinbefore defined),

Thus, according to a further aspect of the invention there are providedprocesses for the preparation of compounds of general formula I, whichcomprise reacting a compound of formula II or an alkali metal saltthereof, with

(a) an alkylating agent of formula ##STR4## (in which X represents achlorine or bromine atom or a sulphonic acid ester group);

(b) an alkylating agent in the form of a 2-propanol of formula ##STR5##(in which Y represents a bromine atom or a sulphonic acid ester group)under formation of HY and subsequently dehydrohalogenating thechlorohydrins thereby formed in the presence of a base; or

(c) an alkylating agent of the formula

    X--CH.sub.2 --CH=CH.sub.2                                  (V)

(in which X is as hereinbefore defined) and the olefin thereby formed isepoxidized.

Reaction of the hydroximic acid esters of formula II with the alkylatingagents of formulae III to V is preferably effected in an anhydrousmedium. Appropriate solvents are, for example, alcohols such asmethanol, ethanol or propanol, and preferably solvents which are inertunder the reaction conditions, e.g. ethers such as dioxan,tetrahydrofuran, diethyl ether, diisopropyl ether or diethylene glycoldimethyl ether; hydrocarbons such as hexane, petroleum ether, benzene,toluene or xylene; halogenated and/or nitrated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride, ethyl chloride orchlorobenzene and/or nitrobenzene; esters such as ethyl acetate; aproticsolvents such as dimethylformamide, dimethylacetamide or dimethylsulphoxide; or, if desired, an excess of the alkylating agentsthemselves.

It is particularly preferred to effect the alkylation with thehydroximic acid esters of formula II in the form of their alkali metalsalts. The alkylation is conveniently effected at a temperature of from0° C. to the boiling point of the solvent. Reaction times are generallyfrom 1 to 5 hours.

Process (a) according to the invention is preferably effected using acompound of formula II in the form of an alkali metal salt thereof whichis reacted with epichlorohydrin.

Dehydrochlorination of chlorohydrins produced in process

(b) is advantageously carried out in a solvent which is inert under thereaction conditions such as, for example, the above-mentioned ethers orhydrocarbons, in the presence of a base, such as, for example, alkalimetal or alkaline-earth metal hydroxides or carbonates, preferablypotassium, sodium or calcium hydroxide or potassium or sodium carbonate,conveniently at temperatures of from 0° C. to 150° C., preferably,however, from 20° to 100° C., and generally within 0.5 to 8 hours.

Epoxidation of the olefin compounds produced in process

(c) can be carried out, for example, with peroxy acids, such as, forexample, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid,monopersuccinic acid, peracetic acid or pertungstenic acid, andpreferably in solvents which are inert under the reaction conditions,such as the above-mentioned solvents, especially chloroform, ethylacetate, ethyl chloride, ethers such as diethyl ether,tetrachloromethane or dimethylformamide. The reaction is convenientlyeffected at a temperature of from -10° to +40° C., and preferably atambient temperature. It has proved especially advantageous to allow thereaction mixture of the olefin and peroxy acid, which is preferably usedin a small excess, to stand at room temperature for up to 24 hours.

Preparation of alkali metal salts of the compounds of formula II used asstarting materials in the processes according to the invention may becarried out, for example, using stoichiometric quantities of alkalimetal hydroxides, carbonates, metals, hydrides, amides, lower alkalimetal alcoholates (in which the alkyl radical has 1 to 4 carbon atoms,e.g. lithium, sodium or potassium methylate, ethylate or tert.butylate)or organometallic compounds, such as butyl lithium, phenyl lithium orphenyl sodium, in the solvents conventionally used therefor, preferablyin hydrocarbons, at temperatures between 0° and 30° C. It has provedparticularly favourable to use sodium methylate in methanolic solutionwith an equivalent quantity at room temperature of the appropriatehydroximic acid ester of formula II which is stirred briefly forapproximately 10 to 60 minutes. Subsequent removal of the solvent bydistillation gives the dry, easily powdered, stable sodium hydroximateswhich, for example, in process (a), are advantageously suspended inepichlorohydrin in a molar ratio of 1: (2-5), whereby a vigorousexothermic reaction takes place which may be optionally effected withcareful heating. To effect completion of this reaction process, themixture may, if desired, be heated for up to 3 or more hours at 105° to115° C. Precipitated sodium chloride may be easily removed by shakingout with water after the addition of excess ether. The pure liquid finalproducts of formula I may be isolated advantageously by fractionaldistillation under reduced pressure.

The surprisingly stable O-(2,3-epoxypropyl)-hydroxylamine derivatives ofgeneral formula I may be obtained in a facile reaction by these singlestage processes and as mentioned above these compounds are good startingsubstances for the synthesis of novel polyfunctionalO-alkylhydroxylamines having interesting pharmacological properties suchas, for example, the compounds described in our copending patentapplication No. 850,057 (corresponding to German Patent Application No.P 26 51 083.8) of the same date, namely, Nov. 9, 1977.

Many hydroxylamine derivatives, some having valuable biologicalproperties, are known. Thus, for example, the preparation has beenreported of some O-(2-hydroxyalkyl)-hydroxylamines, without furtherfunctional groups in the alkyl radical, by the N-hydroxyurethane methodof E. Testa et al. [Helv. Chim. Acta 45, 358,1381 (1962)] and theN-hydroxyphthalimide method of W. Kliegel [Pharmazie 25, 400, 525(1970)].

According to one aspect of the present invention there are providedcompounds of general formula ##STR6## wherein X represents a group ofthe formula ##STR7## in which R¹ represents (a) a hydrogen atom,

(b) an amino group, when X represents an --OR¹ moiety,

(c) an alkyl group having from 1 to 6 carbon atoms or

(d) a mono- or binuclear aryl group optionally substituted by one ormore halogen atoms or alkyl, alkoxy, halogenoalkyl groups each having upto 4 carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms, nitroor cyano groups; and

R² and R³, which may be the same or different, each represents

(a) a hydrogen atom,

(b) an alkyl group having from 1 to 6 carbon atoms or cycloalkyl grouphaving from 3 to 7 carbon atoms and optionally substituted by one ormore hydroxy groups or alkoxycarbonyl groups having 1 to 4 carbon atoms,

(c) an aralkyl or diaralkyl group having 1 to 4 carbon atoms in thealkyl moiety and being optionally substituted in the alkyl moiety byhydroxy groups, and optionally substituted in the aryl moieties by oneor more alkoxy groups having from 1 to 4 carbon atoms or halogen atoms,

(d) a mono- or binuclear aryl group optionally substituted by one ormore alkyl, alkoxy or halogenoalkyl groups each having up to 4 carbonatoms or halogen atoms,

(e) a hydroxy group when the other of R² and R³ is hydrogen, or

(f) R² and R³, together with the nitrogen atom to which they areattached, represent a 5- to 7-membered saturated ring optionallysubstituted by an alkyl group having from 1 to 4 carbon atoms, and thering being optionally interrupted by an oxygen, sulphur or furthernitrogen atom or,

(g) R² and R³, together with the nitrogen atom to which they areattached, represents a 5-membered heteroaromatic ring containing up to 4nitrogen atoms and being optionally formed with a benzene- oruracil-ring

and physiologically acceptable acid addition salts thereof.

Preferred compounds by reason of their favorable pharmacologicalproperties are:

O-(3-phenoxy-2-hydroxypropyl)-hydroxylamine;

O-[3-(p-chlorophenoxy)-2-hydroxypropyl]-hydroxylamine;

O-[3-(2,4-dichlorophenoxy)-2-hydroxypropyl]-hydroxylamine;

O-[3-(3-methylphenoxy)-2-hydroxypropyl]-hydroxylamine;

O-[3-(4-methoxyphenoxy)-2-hydroxypropyl]-hydroxylamine;

O[3-(4-cyanophenoxy)-2-hydroxypropyl]-hydroxylamine;

O[3-(3-trifluoromethylanilino)-2-hydroxypropyl]-hydroxylamine;

O-[3-(4-diphenylmethyl-piperzin-1-yl)-2-hydroxypropyl]-hydroxylamine andphysiologically acceptable acid addition salts thereof.

In the Drawings

FIG. 1 is Formula (I).

FIG. 2 is Formula (II).

FIG. 3 is Formula (III).

FIG. 4 is Formula (IV).

FIG. 5 is Formula (V).

FIG. 6 is Formula (VI).

FIG. 7 is Formula (VII).

FIG. 8 is Formula (VIII).

There is provided the following process for the preparation of compoundsof general formula ##STR8## reacting an O-alkylated hydroxylaminederivative of formula ##STR9## with a compound of formula

    HR.sup.6

to form a common intermediate compound of formula ##STR10## andsubsequently removing the protecting group of formula ##STR11## to forma compound of formula ##STR12##

In the above formulae:

R⁴ represents a straight-chained or branched alkyl group having from 1to 6 carbon atoms or a mono- or binuclear aryl group optionallysubstituted by one or more alkyl or alkoxy groups having up to 2 carbonatoms or halogen atoms;

R⁵ represents a straight-chained or branched alkyl group having from 1to 6 carbon atoms;

R⁶ is as hereinbefore defined for X or represents a group of the formula##STR13## (in which R⁴ and R⁵ are as hereinbefore defined);

Y represents a group of the formula ##STR14## (in which

Z represents a halogen, preferably chlorine or bromine atom, or areactive sulphonic acid ester group).

Example for preparation ofO-[3-(3,4-Dichlorophenoxy)-2-hydroxypropyl]hydroxylamine hydrochloride

A solution of 16.3 g (0.1 mol) of 3,4-dichlorophenol and 10.1 g (0.1mol) of triethylamine in 100 ml of dimethylformamide is mixed with 15.9g (0.1 mol) of ethyl O-(2,3-epoxypropyl)acetohydroximate and thereaction mixture is stirred for 40 hours at 95°-100° C. Aferwards, thesolvent is distilled off under reduced pressure and the residuefractionally distilled under reduced pressure to give 26.2 g (81.3% oftheory) of ethylO-[3-(3,4-dichlorophenoxy)-2-hydroxypropyl]-acetohydroximate of boilingpoint (3 mm Hg) 178°-180° C. To give the hydroxylamine, the distillate(81.3 mmol) is heated in 100 ml of 2N hydrochloric acid for 15 minuteswith reflux, the cooled solution is evaporated to dryness under reducedpressure and the solid residue is recrystallised from ethanol.

Yield: 16.4 g (70% of theory); melting point 152° C. (withdecomposition). C₉ H₁₂ Cl₃ NO₃ (M.W.=288.6)

Analysis: Calculated C 37.46%; H 4.19%; Cl 36.86%; N 4.85%. Found C37.43%; H 4.29%; Cl 36.42%; N 4.83%.

The following Examples serve to illustrate the preparation of compoundsof general formula I. In these Examples the structure of the compoundsproduced has been determined by their elemental analysis, and i.r. and ¹H-n.m.r. spectra.

EXAMPLE 1 Ethyl O-(2,3-Epoxypropyl)-acetohydroximate of formula##STR15## A. By alkylation with epichlorohydrin

To a freshly prepared solution of 11.5 g (0.5 gram atom) of metallicsodium in 300 ml of anhydrous methanol are added, at room temperature,51.5 g (0.5 mol) of ethyl acetohydroximate. The mixture is stirred for30 minutes and the alcohol is distilled off under reduced pressure andwith the exclusion of moisture. After drying at a high temperature in ahigh vacuum the sodium salt residue is suspended in 200 ml (2.5 mol) offreshly distilled epichlorohydrin and slowly heated with vigorousstirring. At approximately 60° C. a vigorous exothermic reaction starts,and the temperature of the mixture rises spontaneously to over 90° C.with the precipitation of sodium chloride. The mixture is maintained for2 hours at 100° to 110° C., left to cool to room temperature, mixed with500 ml diethyl ether and the sodium chloride removed by shaking twicewith 300 ml portions of water. The organic phase is separated and driedover sodium sulphate, the ether is evaporated off in vacuo at roomtemperature and the liquid residue is fractionally distilled underreduced pressure.

Yield: 55 g (69.1% of theory); boiling point (11 mm Hg) 82°-84° C.

    c.sub.7 h.sub.13 no.sub.3 (m.w.=159.2):

Analysis: Calculated: C 52.8%; H 8.25%; N 8.8%. Found: C 52.7%; H 8.5%;N 8.7%.

B. by alkylation with 2,3-epoxypropyl-p-toluene sulphonate

To a suspension of 6.0 g of 80% sodium hydride (0.2 mol) in 200 ml ofdimethylformamide are added with stirring 20.6 g (0.2 mol) of ethylacetohydroximate and the mixture is stirred for 30 minutes at roomtemperature to give a clear solution. The mixture is heated to 50° C.and at this temperature 45.7 g (0.2 mol) of 2,3-epoxypropyl-p-toluenesulphonate in 20 ml of dimethylformamide are added dropwise. The mixtureis subsequently heated with continuous stirring for 1 hour to 80° C.,after cooling the solvent is removed under reduced pressure, the residuemixed with 50 ml of water and the product extracted with diethyl ether.After drying the ether phase over sodium sulphate, the solvent isevaporated off and the oily residue is fractionally distilled underreduced pressure.

Yield: 18.4 g (57.8% of theory); boiling point (15 mm Hg) 85°-87° C.

If the alkylation reaction of the sodium salt of ethyl acetohydroximateis carried out with 2,3-epoxypropyl-p-toluene sulphonate in ethanol assolvent, a yield of only 40% is obtained.

EXAMPLE 2 Methyl O-(2,3-epoxypropyl)-benzohydroximate of formula##STR16##

Analogously to Example 1, 30.2 g (0.2 mol) of methyl benzohydroximateare converted with sodium methylate to the corresponding sodium saltwhich is subsequently reacted with 78 ml (1 mol) of epichlorohydrin.After heating for 3 hours under reflux the mixture is allowed to cool,200 ml of water are added and the reaction product is shaken with 500 mlof diethyl ether. The ether phase is dried over sodium sulphate, thesolvent removed by distillation and the oily residue is fractionallydistilled under reduced pressure.

Yield: 15.9 g (38.4% of theory); boiling point (0.4 mm Hg) 135° to 137°C.

    c.sub.11 h.sub.13 no.sub.3 (m.w=207.3);

Analysis: Calculated: C 63.76%; H 6.32%; N 6.76%. Found: C 63.65%; H6.43%; N 6.98%.

EXAMPLE 3 Ethyl O-(2,3-epoxypropyl)-acetohydroximate of formula##STR17## 1st stage: Ethyl O-allyl-acetohydroximate of formula ##STR18##

To a sodium methylate solution prepared from 11.5 g (0.5 gram atom) ofsodium in 200 ml of anhydrous methanol are added 51.5 g (0.5 mol) ofethyl acetohydroximate. The resulting clear reaction mixture is heatedto 50° C. and then 60.5 g (0.5 mol) of allyl bromide are added dropwise.The mixture is subsequently heated for 1 hour under reflux, then cooled,filtered from sodium bromide precipitated, and the solvent is distilledoff under reduced pressure. The residue obtained is dissolved in 300 mlof diethyl ether. After washing several times with water, drying theorganic phase over sodium sulphate and evaporation of the ether, an oilis obtained which is fractionally distilled under reduced pressure.

Yield: 51 g (71.2% of theory); boiling point (32 mm Hg)

    66°-67° C.; α.sub.D.sup.25 =1.4290.

    c.sub.7 h.sub.13 no.sub.2 (m.w=143.2)

2nd stage: Ethyl O-(2,3-epoxypropyl)-acetohydroximate

A solution of 45 g (0.21 mol) of 80% 3-chloroperbenzoic acid in 250 mlof chloroform is mixed with 26.1 g (0.18 mol) of ethylO-allyl-acetohydroximate. The mixture is then stirred for 24 hours atroom temperature. It is then filtered from 3-chlorobenzoic acidprecipitated, washed with chloroform and residual acid is removed fromthe organic phase by repeatedly shaking with 10% sodium hydroxidesolution. After washing neutral with water, the mixture is dried oversodium sulphate, the solvent evaporated off under reduced pressure andthe oily residue is fractionally distilled.

Yield: 5.7 g (20% of theory), boiling point (15 mm Hg) 84°-86° C.

    c.sub.7 h.sub.13 no.sub.3 (159.2)

of formula VI

Analysis: Calculated: C 52.8%; H 8.25%; N 8.8%. Found: C 52.9%; H 8.40%;N 8.6%.

It is not intended that the examples given herein should be construed tolimit the invention thereto, but rather they are submitted to illustratesome of the specific embodiments of the invention. Resort may be had tovarious modifications and variations of the present invention withoutdeparting from the spirit of the discovery or the scope of the appendedclaims.

What we claim is:
 1. Compounds of general formula ##STR19## wherein R¹represents a radical selected from the group consisting of an alkylgroup having from 1 to 6 carbon atoms and an unsubstituted aryl grouphaving 6 carbon atoms and R² represents an alkyl group having from 1 to6 atoms.
 2. Compounds of general formula I as claimed in claim 1 whereinR¹ represents a radical selected from the group consisting of methyl andphenyl and R² is an alkyl having up to 2 carbon atoms.
 3. EthylO-(2,3-epoxypropyl)-acetohydroximate.
 4. MethylO-(2,3-epoxypropyl)-benzohydroximate.